19-51455501-T-C

Position:

• chr19-51455501-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014442.3(SIGLEC8):​c.968A>G​(p.Glu323Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SIGLEC8 NM_014442.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0980

Genes affected

SIGLEC8 (HGNC:10877): (sialic acid binding Ig like lectin 8) Sialic acid-binding immunoglobulin (Ig)-like lectins, or SIGLECs (e.g., CD33 (MIM 159590)), are a family of type 1 transmembrane proteins each having a unique expression pattern, mostly in hemopoietic cells. SIGLEC8 is a member of the CD33-like subgroup of SIGLECs, which are localized to 19q13.3-q13.4 and have 2 conserved cytoplasmic tyrosine-based motifs: an immunoreceptor tyrosine-based inhibitory motif, or ITIM (see MIM 604964), and a motif homologous to one identified in signaling lymphocyte activation molecule (SLAM; MIM 603492) that mediates an association with SLAM-associated protein (SAP; MIM 300490) (summarized by Foussias et al., 2000 [PubMed 11095983]).[supplied by OMIM, May 2010]

SIGLEC8 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11782339).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGLEC8	NM_014442.3	c.968A>G	p.Glu323Gly	missense_variant	4/7	ENST00000321424.7	NP_055257.2
SIGLEC8	NM_001363548.1	c.689A>G	p.Glu230Gly	missense_variant	3/6		NP_001350477.1
SIGLEC8	XM_011526734.3	c.935A>G	p.Glu312Gly	missense_variant	4/7		XP_011525036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIGLEC8	ENST00000321424.7	c.968A>G	p.Glu323Gly	missense_variant	4/7	1	NM_014442.3	ENSP00000321077.2
SIGLEC8	ENST00000340550.5	c.689A>G	p.Glu230Gly	missense_variant	3/6	1		ENSP00000339448.4
SIGLEC8	ENST00000430817.5	c.641A>G	p.Glu214Gly	missense_variant	2/6	2		ENSP00000389142.1
SIGLEC8	ENST00000597352.1	n.584A>G		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.968A>G (p.E323G) alteration is located in exon 4 (coding exon 4) of the SIGLEC8 gene. This alteration results from a A to G substitution at nucleotide position 968, causing the glutamic acid (E) at amino acid position 323 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	.;T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.00087	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.99	.;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Benign	0.017
Sift	Benign	0.081	T;T;T
Sift4G	Uncertain	0.040	D;T;D
Polyphen		0.28	B;B;B
Vest4		0.20
MutPred		0.47		.;Loss of stability (P = 0.1729);.;
MVP		0.19
MPC		0.15
ClinPred		0.38	T
GERP RS		1.1
Varity_R		0.12
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51958755;